An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non–Small Cell Lung Cancers

Abstract

Background: To directly assess tumor oxygenation in resectable non^small cell lung cancers (NSCLC) and to correlate tumor pO 2 and the selected gene and protein expression to treatment outcomes. Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO 2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO 2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. Results:The median tumor pO 2 ranged from 0.7 to 46 mm Hg (median,16.6) and was lower than normal lung pO 2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO 2 as a reflection of tumor oxygenation. The median T/L pO 2 was 0.13. T/L pO 2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse wereTstage (P = 0.02),T/L pO 2 (P = 0.04), and osteopontin levels (P = 0.001). Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

“…[41][42][43][44][45][46][47][48] Early reports suggested that semiquantitative scoring of CAIX labeling was correlated with direct pO 2 measurements in solid tumors, but this has not been confirmed by other groups. [32][33][34][35][36][49][50][51][52][53] When we examined a series of single punch biopsies obtained from Figure 5 The 95% CI of the averaged per patient % carbonic anhydrase IX (CAIX) value, in full sections (a) and in tissue microarray (TMA) simulations (b and c). Solid black circles indicate averaged % CAIX staining of full sections, crosses-simulated microarray cores, dashed line-95% confidence limits, horizontal reference lines are drawn through 5 and 10% CAIX values.…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…Intratumoral hypoxia in lung cancers correlates with decreased overall survival (Swinson et al 2003;Le et al 2006). Both HIF-1α and HIF-2α are frequently expressed in NSCLC, also during early progression of disease; but whereas HIF-2α causes, or is a surrogate marker for poor clinical prognosis (Giatromanolaki et al 2001), the role of HIF-1α in predicting outcome is debated.…”

HIF-2α deletion promotes Kras-driven lung tumor development

“…D espite the access of normal pulmonary epithelia to atmospheric O 2 levels, tumor hypoxia has been observed in human non-small cell lung cancer (NSCLC) and correlates with poor prognosis and decreased disease-free survival (1,2). Cells can overcome hypoxic stress through multiple mechanisms, including the stabilization of hypoxia inducible factor (HIF) transcriptional regulators.…”